DETAILED ACTION
This Action is in response to the communication filed on 03/05/2026.
Claims 1-2, 4-6, 8-10, 12-15, 17-19, 21-23, 25 are currently pending.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of the species: SARS-CoV-2, antisense oligonucleotide, U6atac snRNA, EXOSC2, in the reply filed on 03/05/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 8-10, 21-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/05/2026.
Claims 1-2, 4-6, 12-15, 17-19, 25 are under consideration.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 4-6, 12-15, 17-19, 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of inhibiting replication of an Ebola virus in a cell in vitro comprising administering Tenovin-1 to a cell infected with an Ebola virus wherein the cell is in vitro, does not reasonably provide enablement for the broadly claimed method which explicitly encompasses a method of inhibiting SARS-CoV-2 in a viral host (including treating a subject having or suspected of having a SARS-CoV-2 infection comprising administering to the viral host an antisense oligonucleotide that inhibits U6atac snRNA (i.e., the elected species). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In making a determination as to whether an application has met the requirements for enablement under 35 U.S.C. 112 ¶ 1, the following factors enumerated In re Wands, 8 USPQ2d 1400, at 1404 (CAFC 1988) are considered: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
It should be made clear that, the enabling specification must teach those skilled in the art to make and use the full scope of the claimed invention without undue experimentation. “Although not explicitly stated in section 112, to be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without "undue experimentation." Vaeck, 947 F.2d at 495, 20 USPQ2d at 1444; Wands, 858 F.2d at 736-37, 8 USPQ2d at 1404; In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (the first paragraph of section 112 requires that the scope of protection sought in a claim bear a reasonable correlation to the scope of enablement provided by the specification).” In re Wright (CAFC) 27 USPQ2d 1510 at 1513. Although a working example is not required to enable an invention, the skilled artisan must be able to practice the claimed invention without undue experimentation. See also, MPEP §2164.02, which states in part: The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970). Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
The claims are broadly drawn to a method of inhibiting replication of an RNA/DNA virus in a viral host, comprising contacting the viral host with a minor spliceosome inhibitor and inhibiting the replication of the RNA/DNA virus, wherein the RNA/DNA virus interacts with minor intron- containing genes (MIGs) in the viral host (see claim 1). The claims with respect to the elected species are limited to a method of inhibiting replication of SARS-CoV-2 in a viral host comprising administering to the viral host an antisense oligonucleotide that inhibits U6atac snRNA.
The specification discloses a working example where isolated HEK 293 cells are treated with Tenovin-1 which resulted in downregulation of U11, U12, U4atac snRNA, and U6atac snRNA (see Example 2, paragraph [0053]), as well as treating isolated Huh7 cells (in vitro) with Trenovin-1 and infecting the cells with an Ebola virus that expresses GFP with Trenovin-1 resulting in inhibition of GFP expression in the cells, indicating inhibition of Ebola replication in the cells (see Example 3 beginning at paragraph [0054]). The specification does not provide any in vivo examples, nor does it provide any examples providing evidence that an antisense oligonucleotide targeting U6atac snRNA would have an inhibitory effect on any virus, nor are there examples demonstrating that a spliceosome inhibitor can be used to inhibit SARS-CoV-2 replication in any cell neither in vitro nor in vivo.
It is noted that although the evidence presented indicates an inhibitory of effect of Tenovin-1 on Ebola virus replication in a host cell in vitro, there is no evidence indicating that Tenovin-1 treatment would have any affect on SARS-CoV-2 replication, or any other virus, in a host cell, in vitro or in vivo, which is essential considering that Ebola virus and SARS-CoV-2 are unrelated viruses and the effect on Ebola (a filovirus) is not predictable of the same effect on SARS-CoV-2 (a coronavirus) as they differ drastically in how they spread, their mortality rates, and the human body systems they target. While both can cause severe illness, SARS-CoV-2 is an airborne respiratory disease with a high spread rate and low mortality, whereas Ebola is a contact-transmitted hemorrhagic illness with a high mortality rate and low spread rate.
Looking to the prior art for guidance, a search of the prior art did not identify any methods of inhibiting replication of SARS-CoV-2 in a viral host comprising administering to the viral host an antisense oligonucleotide that inhibits U6atac snRNA (the elected species), nor does the prior art appear to teach using antisense oligonucleotides directed to any minor spliceosome protein-encoding RNA to inhibit SARS-CoV-2 replication.
Therefore, given the lack of knowledge present in the prior art and the lack of guidance provided in the specification with respect to, further experimentation would be required. Considering that the additional experimentation would require de novo experimentation without a guarantee of success, and further considering that any positive results would amount to a significant advancement in the state of the art, the additional experimentation required is considered undue.
It is noted that therapeutic experimentation often begins with in vitro studies as proof of principle before moving to in vivo experimentation to determine therapeutic efficacy. As indicated above, in the instant case there is no in vivo or in vivo experimental data provided for treatment of SARS-COV-2 in a host cell using any antisense oligonucleotide targeted to U6atac snRNA or any other minor spliceosome element. It is acknowledged, as indicated above, that the specification discloses in vitro treatment of HEK 293 cells with Tenovin-1 which results in downregulation of U11, U12, U4atac snRNA, and U6atac snRNA, as well as treating isolated Huh7 cells (in vitro) with Trenovin-1 and infecting the cells with an Ebola virus that expresses GFP resulting in inhibition of GFP expression indicating inhibition of Ebola replication in the cells, but this is not sufficient to enable the instant claimed method. Even though the in vitro data enables inhibiting Ebola replication in a cell in vitro using Tenovin-1, this does not enable in vivo embodiments encompassed by the claims because the prior art teaches that in vitro results do not necessarily predict in vivo results and further experimentation is required. For instance, Ghallab (EXCLI Journal, 2013; 12:1024-1026) teaches,
“One reason why it is difficult to establish in vivo relevant in vitro systems is that isolated and cultivated primary cells usually differ strongly from the corresponding cell type in an organism. For example, when primary hepatocytes are isolated from their normal microenvironment hundreds of genes are up or down regulated. Although not impossible it is technically challenging to establish culture conditions under which at least some of the deregulated genes return to in vivo like levels.
Other reasons why the replacement of animal experiments is difficult are (1) difficulties to include xenobiotic metabolism into in vitro assays, (2) difficulties to capture interactions between different cell types, (3) problems to extrapolate from in vivo doses to in vitro concentrations, (4) difficulties in simulating the consequences of long term exposures in vitro, (5) difficulties in extrapolating from perturbed pathways or biomarkers in vitro to adverse effects in vivo.
However, a further critical aspect may have been underestimated in the recent discussion about possibilities and limitations of in vitro systems. Due to their complex architecture and organization organs have possibilities to compensate stress situations that may be lost in vitro.
Unfortunately, we are still far from being able to simulate complex situations such as microarchitecture and compartmentation of organs. It may be possible to fully replace animal experiments by in vitro systems in future. This will be the case when we (i) have understood all relevant mechanisms of toxicity, interactions between cell types and organs including their compensatory mechanisms, (ii) have established in vitro systems that correctly recapitulate all mechanisms. The time horizon for such ambitious goals will be rather centuries than decades.” (Emphasis added, citations removed).
Regarding oligonucleotide efficacy in vivo, Kawakami et al. (Journal of Pharmaceutical Sciences, 2008; 97(2):726-745) teaches that although pDNA and ODN are novel candidates for nonviral gene therapy, their clinical applications are generally limited owing to their rapid degradation by nucleases in serum and rapid clearance (See abstract). Kawakami states that rapid elimination is observed after injection of oligonucleotides due to uptake by the liver, degradation by nucleases, and urinary excretion (p.735 last paragraph) and further indicates that to date, there are very few reports of targeted oligonucleotide delivery (first paragraph on p.738).
Additionally, Braasch et al. (Biochemistry, 2002; 41(14):4503-4510) emphasizes that major obstacles persist in the art: “gene inhibition by antisense oligomers has not proven to be a robust or generally reliable technology. Many researchers are skeptical about the approach and it has been suggested that many published studies are at least partially unreliable” (Pg. 4503, para. 1 and 2). Braasch et al. goes on to identify factors that contribute to the unpredictable efficacy of antisense compounds in vivo: poor antisense oligonucleotide access to sites within the mRNA to be targeted, difficulties with delivery to and uptake by cells of the antisense oligos, toxicity and immunological problems caused by antisense oligos, and artifacts created by unpredictable binding of antisense compounds to systemic and cellular proteins. Regarding the difficulties of predicting whether antisense oligonucleotides can access sites within their target mRNA, Braasch et al. explains, “it has been difficult to identify oligonucleotides that act as potent inhibitors of gene expression, primarily due to difficulties in predicting the secondary structures of RNA (Pg. 4503, para. 1 and 2). Branch adds that “internal structures of target RNAs and their associations with cellular proteins create physical barriers, which render most potential binding sites inaccessible to antisense molecules” (Page 45, third column).
Further, Branch, in the article “A good antisense is hard to find” (Branch, Trends in Biochemical Sciences, 1998; 23:45-50) states that “the value of a potential antisense drug can only be judged after its intended clinical use is known, and quantitative information about its dose-response curves and therapeutic index is available” (Page 46, second column).
It is noted that Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: "Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention." Such is the case here where the application discloses a very narrow embodiment of the broadly claimed method which is essentially a mere germ of the idea of broadly claimed method which encompasses inhibiting SARS-CoV-2 replication in a host cell, including in vivo, which the prior art indicates presents many obstacles which must be overcome. Thus, in view of the reasons set forth above, it would take an undue amount of experimentation for one of skill in the art to practice the full scope of the claimed invention.
Furthermore, in In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, as described above, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims.
Therefore the instant rejection under 35 USC 112(a) is appropriate. It is noted that limiting the claims to that which identified as the scope of the claims which is enabled (as indicated above) would obviate this rejection.
Conclusion
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J. E. Angell
Primary Examiner
Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
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